At present, Palbociclib & trastuzumab both anticancer agents have prominent use in breast cancer treatment. Palbociclib is used in human receptor positive (HR+), human epidermal growth negative HER2 breast cancer, whereas trastuzumab is used against HER2+ breast cancer treatment. These two comprehensive drugs have shown a great potential in treating metastatic breast cancer as well as have shown a greater patient safety & efficacy profile than many other conventional treatment regimens.
We have reviewed three research articles for the mechanism of action, patient review for palbociclib. And another three research articles were reviewed for mechanism of action, safety profile of palbociclib. Other information regarding breast cancer were collected from different authentic websites.
Symptoms of Breast Cancer
Nipple of the breast can move from its place and sometimes blood discharge can occur.
One part of the breast can be swelled or whole breast can be swelled.
Painful breast with an extreme fondness can occur.
Uncomfortable feeling and inflammation along with redness can be seen in both of the breasts.
Sometimes clump formation can occur in any part of the breast. In future it can be converted into tumor.
Lump can also form under the armpits.
Types of Breast Cancer
Breast cancers are mainly invasive and noninvasive. Invasive means the cancer can come out of its affected area and can affect its surrounding tissues. On the other hand, noninvasive breast cancer stays in their affected area and does not come out of milk duct or lobules of the breast. Tow important type of breast cancers are-
Ductal carcinoma: This cancer is happened in the milk duct and it is responsible for many other breast cancers.
Ductal carcinoma In Situ (DCIS): This cancer is located in its ductal area.
Invasive or Infiltering Carcinoma: This cancer spreads out of its ductal area and can affect its adjacent tissues.
Lobular carcinoma: lobules of the breast is affected by this type of cancer.
Lobular Carcinoma In Situ (LCIS): This cancer is located inside the lobules.
Invasive Lobular Carcinoma: This cancer spreads out of its lobules and can affect its adjacent tissues.
We cannot say that Breast cancer is a single disease, even among the same type of breast cancer. Three main subtypes belong to the breast cancer which can be determined through special tests on a sample of the tumor.
1. Hormone Receptor Positive: Estrogen receptors and/or progesterone receptors expressing breast cancers are known as ‘Hormone receptor positive’. They are proteins found in and on cells. Tumors with estrogen receptors are known as ‘ER-positive’, and with progesterone receptors are called ‘PR-positive’. About 60% to 75% of breast cancers are involved in this subtype. Hormone receptor negative are those cancers which have not the above receptors.
2. HER2 positive: 15% to 20% of breast cancers depend on the human epidermal growth factor receptor 2(HER2) for growing. These cancers have many copies of the Her2 gene or high level of the HER2 protein and they are known as ‘HER2 positive’. HER2 negative are those whose have less amount of HER2 protein or few copies of HER2 gene. HER2 protein are made by HER2 gene and the proteins are found on the cancers cell, responsible for tumor cell growth.
3. Triple negative: The tumor who does not express ER, PR and/or HER2, are known as ‘triple negative’. They make up about 15% of invasive breast cancers. They are more common among younger black women. They are also seen in women with a mutation in breast cancer genes, BRCA1 and BRCA2.
After appearing the symptoms, breast cancers are being identified. For that reason regular breast cancer screening is necessary.
Imaging Tests: They include-
a) Mammograms: An X-ray picture of the breast which is used by the doctors to look for early signs of breast cancer.
b) Breast Ultrasound: It is the medical ultrasonography to perform imaging of the breast.
c) Breast MRI: Magnetic resonance imaging (MRI) of the breast uses a powerful magnetic field, radio waves and a computer to produce whole pictures of the structures within the breast.
Biopsy: A biopsy is being done for the final assurance of breast cancer. It is a test that removes tissue or fluids from the suspicious area. The removed cells are examined through a microscope and further tested to check for the presence of breast cancer.
Diagnosis of Advanced Breast Cancer Specially HER2 Positive or Negative
Immuno-histochemical Staining (IHC): This diagnosis process is one of the sub-types of immune-histochemistry. Here the principle is based on antigen-antibody binding reactions. Fluorescent markers are conjugated with specific antigens. When these antigens are bound with antibodies, these can be detected under fluorescent microscopes. IHC is more popular because of its high specificity.
Fluorescence In Situ Hybridization (FISH Test): Specific gene mapping is done during the biopsy of breast tumors to see if HER2 receptors are present. RNA probes are injected around the tumor cells to visualize if specific HER2 proteins are synthesized within the tumor cells.
PalbociclibBrand Name: IbranceDeveloper: Pfizer
Palbociclib is a drug that is used for the treatment of metastatic breast cancer. This drug works on human receptor positive (HR+) and human epidermal growth factor negative (HER-) metastatic breast cancer (MBC). Palbociclib is a pyridopyrimidine that is orally active. It is a highly selective reversible CDK4/6 inhibitor.
Mechanism of Action of Palbociclib
Palbociclib is a selective inhibitor of cyclin-dependent kinases (CDK4/CDK6). This CDK is dependent on cyclin D protein for its normal activity. CDK4 and CDK6 are serine kinases. These kinases are upregulated in several tumor cell types. They play a significant role in regulating cell cycle.
CDK4/CDK6 when binds with cyclin D protein they induce phosphorylation of retinoblastoma protein (Rb-protein). This Rb protein is a tumor suppressor protein which inhibit the cell proliferation by arresting the cell into the G1-phase and the cells cannot transit from G1 to S phase. When cycline D and CDK form a complex it ultimately inactivates the Rb protein by phosphorylation and instigates the E2F transition factor (TF). This TF factor leads to cell transition from G1 to S phase. Thus, cell is divided and proliferated.
Palbociclib acts on the CDK4/6 and causes reduced Retinoblastoma phosphorylation. As a result, there is a reduced expression of E2F transition factor. This ultimately incite signals that leads to cell cycle arrest. So, the cells will not be transited into S-phase, DNA proliferation will be inhibited. This will result in inhibition of cancer cell proliferation.
Palbociclib is administered with antiestrogens for better treatment.
Fig. Mechanism of Action of PalbociclibPharmacokinetics Profile of PalbociclibAbsorption
Following oral administration, Cmax the mean maximum observed concentration of this drug was noticed between 6 to 12 hours. It was observed that area under curve (AUC) and Cmax enhanced proportionally with dose in the dosing range of 25mg to 225mg.
Food effect: under fasting condition palbociclib absorption and exposure was observed very low. Palbociclib absorption was increased by food intake. So, it is advantageous to administer palbociclib with food.
Palbociclib binds to human plasma protein very effectively and the observed value was approximately 85%
After the in vivo and in vitro studies it was obtained that palbociclib is metabolized in the liver. Mainly oxidation and sulfonation and acetylation and glucuronidation being the minor pathways.
Major route of elimination was feces about 71.4% of dose while 17.5% of the dose was recovered in urine. Majority of the product was eliminated as metabolites.
Stomatitis: is a condition where inflammation of oral cavity and mouth occurs
Thrombocytopenia: is a disorder that is characterized by lower level ofthrombocytes in our body.
Neutropenia: characterized by low level of neutrophils in blood.
Upper respiratory infection_ is very rare but when occurs it takes a drastic form.
Peripheral neuropathy- nerve damage of the peripheral system.
Pulmonary embolism: occurs when embolus forms in the lungs.
Patient Compliance & Safety Profile of PalbociclibPalbociclib is available only for three years as it was approved in 2015 by US FDA. So, very little is known about its patient compliance. But from the study we have come to know that cancer therapy satisfaction questionnaire (CTSQ) which is owned by Pfizer has done a study on palbociclib adjuvant therapy to find out its patient compliance. This study gives a clear view on palbociclib therapeutic efficacy with other drugs as well as patient compliance. This study was done in six countries in a real-world setting.
center165200Fig. CTSQ Scores of PalbociclibThere were three categories, those were the basis of the CTSQ scores. They are given below:
Cancer Spreading: Palbociclib stopped cancer from spreading or metastasize in more than 62% of the patients of breast cancer.
Expectations Profile: Palbociclib therapy showed that the patients reported expectations met was more than 96% of the total population.
Side Effects Profile: Palbociclib therapy side effects were better than expected was in more than 92% population overall.
The overall CTSQ score showed that palbociclib therapy with other adjuvant cancer medications resembled one of the most-safer drugs of breast cancer treatment regimens. So, the drug is one of the best drugs available in the market under HR positive HER2 negative treatment regimens.
Another study we found was conducted to show the overall survival level of palbociclib therapy with other adjuvant cancer therapy. The study was done in about 413 breast cancer affected women. They all were diagnosed with HER2 negative breast cancer. So, the therapy they were prescribed consists with palbociclib.
center-190500Fig. Survival Rate of PalbociclibDuring the study, it was found that from 413 postmenopausal patients, 95% patients survived 34.8 months more than other treatment regimens. Palbociclib and fluvestrant were in the combination therapy. On the other hand, the study was also conducted in 108 premenopausal women, where the result showed that, more than 95% patients survived 38 more months than other therapeutic regimens of breast cancer.
Brand Name: Herceptin
Trastuzumab is a drug that is used for the treatment of metastatic breast cancer. This drug works on human receptor positive (HR+) and human epidermal growth factor positive (HER+) metastatic breast cancer (MBC). Trastuzumab is a monoclonal antibody, used with docetaxel and carboplatin called ‘TCH’ regimen.
Mechanism of Action of HER Receptor on Tumor Cells
When the HER proteins activate, it signals for rapid cell growth. HER proteins are over expressed in tumor cells, especially in breast cancer cells. There are 4 types of HER protein. HER1, HER2, HER3 & HER4 receptors.
HER receptor consists of:
Receptor specific ligand domains.
Plasma membrane domain.
Intracellular tyrosine kinase domain.
Fig. Normal Mechanism of Action of HER2 Receptor
When a specific receptor ligand binds with the receptor, homodimerization or hetero-dimerization occurs among the HER proteins and this will cause the phosphorylation in the intracellular tyrosine kinase domain. The phosphorylated domain of HER2 activates lipid kinase phosphoinositide-3 kinase which will phosphorylate the enzyme AK transforming factors (AK+). On the other hand, the guanine nucleotide exchange factor and mammalian homologue of the son of seven-less (SOS) activates the Rat sarcoma (RAS) enzyme. This will activate receptor activation factor (RAF) and mitogen-activated protein kinase (MAPK) and mitogen extracellular signal kinase (MEK).
These two simultaneous activations will ultimately induce cell proliferation and cell growth, also signal to VEGF (vascular endothelial growth factor) to produce more vessel to feed the new cells.
Mechanism of Action of Trastuzumab
Trastuzumab induce the cleavage of the extracellular domain of HER receptors or it may bind with the HER2 receptors and prevents homodimerization. If the HER2 receptor cleaves, it leaves a phosphorylated P95 residue.
Fig. Mechanism of Action of Trastuzumab
When the HER2 cannot form dimers, the activation of antibody dependent cell-mediated cytotoxic, which will cause the lysis of tumor cells.
And the HER2 receptor is finally degraded by intracellularly.
Pharmacokinetic Profile of Trastuzumab
Trastuzumab is administered by intravenous infusion and in a week or three weeks schedule. Trastuzumab is degraded intracellularly and it is metabolized into peptides and amino acids. The metabolism is mediated by epithelial cells. The elimination is dependent on the clinical status of the patient and plasma complex. The half-life of the trastuzumab is approximately 28 days. Renal excretion of trastuzumab is very low.
Adverse effects of Trastuzumab
Chronic heart failure
Patient Compliance & Safety Profile of Trastuzumabcenter47974100A trial study was done in a specific group of patients, all affected by advanced stages of breast cancer. Eventually, those patients were given trastuzumab cycle therapy.
center2650490Fig. Patient Survival Rate of Trastuzumab
00Fig. Patient Survival Rate of Trastuzumab
Basis of the study was to show that the trastuzumab therapy leads to increase the survival rate in advanced breast cancer patients.
Total 2571 patients were selected. All of them were diagnosed with hormone receptor positive (HR+), HER2+ breast cancer. Their chemotherapy cycle was ongoing after surgical procedures were done. Chemotherapy included anthracycline antibiotics and taxanes.
The final result of the study showed that the median survival time was increased more than 8 months in advanced breast cancer patients, where among 2571 patients 884 (52%) patients survived in disease free condition more than 2 years of time period after 1 year of trastuzumab cycle therapy.
So, this study showed the efficacy of trastuzumab in a real-world setting.
Case Study on Trastuzumab Therapy Related to Adverse Effects
Life threatening lung complications are highly common side adverse effects of monoclonal antibody used as anticancer agents. The most common form of the lung adverse effect is pneumonitis. Pneumonitis is a non-infectious inflammation of the lung where the inflammatory mediators of the human body are stimulated on drug action. There is a study we found which was done basis on a case of a 67 years old HER2 positive breast cancer patient.
The patient had diagnosed with stage-3 breast cancer, HER2 positive, ER positive, the cancer was spread into left armpit. She was gone through the surgery of lymph node, lumpectomy. After the surgery, pathological procedures showed that, the ductal carcinoma was still invasive. As a result, she was prescribed with radio therapy along with monoclonal antibody, Trastuzumab.
After six weeks, she started the regimen TCH cycle consisting trastuzumab, carboplatin and docetaxel. On day 14 of the treatment, when she was having her 5th cycle, she developed a severe cough. She needed to hospitalize, where she had gone through CT scan and MRI but no infection was shown on those test procedures. Eventually, she developed pneumonitis. She was then treated with prednisone to recover from her pneumonitis, 40mg daily dose along with cyclophosphamide.
After re-starting the TCH cycle, again she developed pneumonitis. This time doctor prescribed her trastuzumab and letrozole combination withdrawing the docetaxel & carboplatin. As a result, she never developed pneumonitis again and she completed whole 21 cycles of trastuzumab therapy with letrozole.
Based on this event, a study was conducted in 1672 breast cancer affected patients, everyone diagnosed with HER2 positive. They all were given trastuzumab with letrozole. 4 patients developed interstitial pneumonitis and 1 of them died, where other patients did not show any kind of adverse effects. The overall affected patients positive result was 0.5%.
Finally, the safety profile and efficacy of trastuzumab is established by this particular study.
From the study, we get knowledge about the HR positive breast cancer drugs that are very much specific in case of their activity. We can also get a clear conception which risk factor are responsible for this disease. A matter of sorrow that in our country the women are not comfortable for diagnosis or treatment for this particular disease. There is a tendency to hide this. So, raising awareness regarding this disease, its signs, symptoms is a burning issue.